Neuroangiogenesis is a term used to describe the coordinated growth of nerves and blood vessels. The nervous and blood vessel systems share guidance cues and cell-surface receptors allowing for this synchronised growth. This term only came into use in 2002 and the process was previously known as neurovascular patterning. The combination of neurogenesis and angiogenesis is an essential part of embryonic development and early life. It is thought to have a role in pathologies such as endometriosis, brain tumors, and Alzheimer's disease.
Neurovascular development is the parallel emergence and patterning of the nervous system and the vascular system during embryogenesis and early life. Neurovascular congruency appears to be determined by shared molecular patterning mechanism involving axon guidance that involves axonal guidance molecules such as sema3A (semaphorin 3A) and (neuropilin).
Neuronal growth cones are situated on the tips of nerve cells and are responsive to different factors, both positive and negative. Growth of the neuron occurs by an extension of the actin (red in image) and microtubule (green in image) cytoskeleton.
Tip cells found at the extremity of the developing blood vessel control adjacent endothelial cells to direct growth. Tip cells have receptors and ligands via which they respond to local neuroangiogenic factors.
There are many neuroangiogenic factors, some of which act to promote neuronal growth and vice versa. The table shows examples
|Neuroangiogenic factor||Effect on neuron||Effect on vascular endothelial cells||Receptor/Ligand||Origin|
|IGF-1||Promotion of neurogenesis and synaptogenesis||EC proliferation, migration, and differentiation||Ligand||Liver cells|
|bFGF||Proliferation of cortical progenitors and neurogenesis||EC proliferation, migration, and differentiation||Ligand||Adipocytes|
|NGF||Neuron survival, differentiation||Promotion of angiogenesis and arteriogenesis in ischemic hindlimbs||Ligand||Multiple|
|Neuropilin||Axon guidance||Synergistic action of VEGF165 in EC migration and proliferation
|VEGF||Neuronal development and patterning, and has neurotrophic and neuroprotective effects||Induces angiogenesis, promotes endothelial cell survival, proliferation and migration||Ligand||Multiple|
Neuroangiogenesis is implicated in a number of pathologies, including endometriosis, brain tumors, and senile dementias, such as Alzheimer's disease. Each of these incurs a significant cost for the healthcare industry, meaning that complete understanding of processes involved – including neuroangiogenesis – is necessary to enable development of functional treatments.
Endometriosis is a common gynaecological disease caused by endometrial tissue implanting outside the uterus, a symptom of which is chronic pelvic pain. The formation, growth and persistence of these implants are dependent upon angiogenesis to increase the supply of blood vessels. The resulting increase in blood flow may correlate directly with pain symptoms. One possible explanation for this is the simultaneous growth of neurons into these areas alongside blood vessels through neuroangiogenesis.
Following ischemic stroke or traumatic brain injury, angiogenesis supports oxygen and nutrient re-supply to injured tissue, and stimulates neurogenesis and synaptogenesis, particularly in the ischemic penumbra. Neuroangiogenesis is finely regulated and sequential, involving proliferation and migration of endothelial cells to restore blood-brain barrier function, recruitment of pericytes, and stabilization new blood vessels, a process dependent on upregulation of proangiogenic factors, such as VEGF and angiopoietin-1.
A condition possibly resulting from a reduction in neuroangiogenic factors is Alzheimer’s disease. Without continued neuroangiogenesis during aging, areas of the brain may no longer have the full complement of functional capillaries and hence, by inference, cerebral blood flow and cognitive ability decline. This condition of reduced neuroangiogenesis and lower capillary density during senescence, possibly involving impaired regulation of angiogenic factors by hypoxia, could be a vascular basis for Alzheimer's disease.
- Greaves, E; Collins, F; Esnal-Zufiaurre, A; Giakoumelou, S; Horne, A. W.; Saunders, P. T. (2014). "Estrogen receptor (ER) agonists differentially regulate neuroangiogenesis in peritoneal endometriosis via the repellent factor SLIT3". Endocrinology. 155 (10): 4015–26. doi:10.1210/en.2014-1086. PMID 25051436.
- Park; et al. (2002). "Delayed Up-regulation of Vascular Endothelial Growth Factor and flk-1 after Global Cerebral Ischemia in Mongolian Gerbil -Possible roles in neuroangiogenesis?" (PDF). Korean Neurological Association. Retrieved 30 September 2015.
- Bautch, V. L.; James, J. M. (2009). "Neurovascular development: The beginning of a beautiful friendship". Cell Adhesion and Migration. 3 (2): 199–204. doi:10.4161/cam.3.2.8397. PMC . PMID 19363295.
- Asante, A; Taylor, R. N. (2011). "Endometriosis: The role of neuroangiogenesis". Annual Review of Physiology. 73: 163–82. doi:10.1146/annurev-physiol-012110-142158. PMID 21054165.
- Vallon M, Chang J, Zhang H, Kuo CJ (2014). "Developmental and pathological angiogenesis in the central nervous system". Cell Mol Life Sci. 71 (18): 3489–3506. doi:10.1007/s00018-014-1625-0. PMC . PMID 24760128.
- Ambrose, C. T. (2012). "Neuroangiogenesis: A vascular basis for Alzheimer's disease and cognitive decline during aging". Journal of Alzheimer's Disease. 32 (3): 773–88. doi:10.3233/JAD-2012-120067 (inactive 2017-01-20). PMID 22850316.
- Bates, D; Taylor, G. I.; Minichiello, J; Farlie, P; Cichowitz, A; Watson, N; Klagsbrun, M; Mamluk, R; Newgreen, D. F. (2003). "Neurovascular congruence results from a shared patterning mechanism that utilizes Semaphorin3A and Neuropilin-1". Developmental Biology. 255 (1): 77–98. doi:10.1016/s0012-1606(02)00045-3. PMID 12618135.
- Park, J. A.; Choi, K. S.; Kim, S. Y.; Kim, K. W. (2003). "Coordinated interaction of the vascular and nervous systems: From molecule- to cell-based approaches". Biochemical and Biophysical Research Communications. 311 (2): 247–53. doi:10.1016/j.bbrc.2003.09.129. PMID 14592405.
- Morotti, M; Vincent, K; Brawn, J; Zondervan, K. T.; Becker, C. M. (2014). "Peripheral changes in endometriosis-associated pain". Human Reproduction Update. 20 (5): 717–36. doi:10.1093/humupd/dmu021. PMC . PMID 24859987.
- Ambrose, C. T. (2016). "The Role of Capillaries in the Lesser Ailments of Old Age and in Alzheimer's Disease and Vascular Dementia: The Potential of Pro-Therapeutic Angiogenesis". Journal of Alzheimer's Disease. 54 (1): 31–43. doi:10.3233/JAD-160303. PMID 27392865.